A single-arm phase II trial of SAcituzumab govitecan and Trastuzumab for HER2+ metastatic breast cancer after Trastuzumab DEruxtEcaN (SATEEN)

This research study is being done to evaluate the safety and effectiveness of sacituzumab
govitecan with trastuzumab (Herceptin, Herceptin Hylecta, or trastuzumab biosimilar) in
metastatic HER2+ breast cancer.

The names of the study drugs used in this research study are:

- Sacituzumab govitecan (a type of antibody-drug conjugate)

- Trastuzumab (Herceptin) (a type of monoclonal antibody)

- Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta) (a type of recombinant
monoclonal antibody)

- Trastuzumab biosimilar drug

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed invasive breast
cancer, with unresectable locally advanced or metastatic disease. Patients without
pathologic or cytologic confirmation of metastatic disease should have unequivocal
evidence of metastasis from physical examination or radiologic evaluation.

- At least one measurable lesion that can be accurately assessed at baseline by CT
(MRI where CT is contraindicated) and is suitable for repeated assessment as per
RECIST 1.149 (see Section 11).

NOTE: If the only site of measurable of disease has been previously irradiated, there
must be evidence of post-radiation progression.

- Either the primary tumor or the metastasis (or both) must be HER2+ per ASCO/CAP 2018
guidelines.1 Central confirmation of HER2 status is not required.

- Any ER and PR expression are permitted but must be known.

- Participants must have received prior treatment with a taxane, trastuzumab, and
T-DXd. These agents may have been administered in the curative or the advanced
setting. Prior progression on these agents is not required. T-DXd does not need to
be the most recent prior therapy.

- Participants must have discontinued all chemotherapy, biologic treatment or
investigational agent at least 14 days prior to study treatment initiation (any
prior endocrine therapy does not require washout).

- All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade
1 or lower, except alopecia can be any grade and neuropathy can be grade 2 or lower.

- Participants on bisphosphonates or RANK ligand inhibitors may continue receiving
therapy during study treatment and also may initiate therapy with these agents on
study if clinically indicated.

- Prior radiation therapy must be completed at least 7 days prior to study treatment
initiation, and all toxicities related to prior radiation therapy must have resolved
to CTCAE v5.0 grade 1 or lower, unless otherwise specified in 3.1.14.

- Previously treated brain metastases are permitted, with the following provisions:
(1) Prior SRS should be completed ≥ 7 days before study treatment initiation; (2)
Prior WBRT should be completed ≥ 7 days before study treatment initiation. (3) Any
corticosteroid use for brain metastases must have been discontinued for ≥ 7 days
prior to study treatment initiation.

- Pre- and postmenopausal women or male patients ≥ 18 years old.

- ECOG performance status of 0 - 2 (Karnofsky > 50%).

- Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or
multigated acquisition (MUGA) scan.

- Participants must have normal organ and bone marrow function as defined below:

- Absolute neutrophil count ≥1,000/mcL

- Platelets ≥100,000/mcL

- Hemoglobin ≥ 9.0 g/dl

- INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as
long as PT or aPTT is in therapeutic range of anticoagulant

- Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN
in patients with documented Gilbert's Syndrome)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or

≤5 × institutional ULN for participants with documented liver metastases

- Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/
1.73m2 for participants with creatinine levels above institutional ULN.

- Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test within 2 weeks prior to study treatment initiation. Childbearing
potential is defined as participants who have not reached a postmenopausal state (≥
12 continuous months of amenorrhea with no identified cause other than menopause)
and have not undergone surgical sterilization (removal of ovaries and/or uterus).

- WOCBP must agree to use an adequate method of contraception. Contraception is
required starting with the first dose of study medication through 7 months after the
last dose of study medication. Examples of contraceptive methods with a failure rate
of < 1% per year include bilateral tubal ligation, male sterilization,
hormone-releasing intrauterine devices, and copper intrauterine devices. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception (Appendix C).

- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment 7 months after the
last dose of study treatment.

- Participants must be willing to undergo a research biopsy at baseline. If disease is
not safely accessible according to the treating investigator, permission to waive
the mandatory baseline biopsy must be received from the sponsor-investigator.
Patients must be willing to provide archival tissue for research purposes.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Prior therapy with any Trop-2 directed ADC, including sacituzumab govitecan.

- Prior hypersensitivity to trastuzumab, sacituzumab govitecan, or the excipients of
trastuzumab or sacituzumab govitecan.

- Known history of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28 allele homozygosity,
which is associated with increased risk for neutropenia and diarrhea related to
irinotecan.50 UGT1A1 genotyping is not required for eligibility.

Note: Concurrent administration of strong UGT1A1 inhibitors or inducers is not allowed
during the study (See Section 5.5).

- Known brain metastases that are untreated, symptomatic, or require corticosteroid
therapy to control symptoms.

- Known leptomeningeal disease.

- Major surgery within 2 weeks prior to study treatment initiation. Patients must have
recovered from any effects of any recent major surgery.

- Individuals with a history of a second malignancy are ineligible except for the
following circumstances:

- Individuals with a history of other malignancies are eligible if they have been
disease-free for at least 3 years or are deemed by the investigator to be at
low risk for recurrence of that malignancy.

- Individuals with the following cancers that have been diagnosed and treated
within the past 3 years are eligible: cervical/prostate carcinoma in situ,
superficial bladder cancer, non-melanoma cancer of the skin.

- Patients with other cancers diagnosed within the past 3 years and felt to be at
low

- risk of recurrence should be discussed with the study principal investigator to
determine eligibility.

- Uncontrolled, significant intercurrent or recent illness including, but not limited
to, ongoing or active infection, uncontrolled non-malignant systemic disease,
uncontrolled seizures, or psychiatric illness/social situation that would limit
compliance with study requirements in the opinion of the treating investigator.

- Participants who are pregnant or breast-feeding are not eligible for enrollment.